Toxicity Evaluation of Toxicity Evaluation of Chemicals with Limited Chemicals with Limited

Toxicity DataToxicity DataRoberta L. Grant, Ph.D.Roberta L. Grant, Ph.D.

Toxicology Division - Chief Engineer’s OfficeToxicology Division - Chief Engineer’s OfficeTexas Commission on Environmental QualityTexas Commission on Environmental Quality

OutlineOutline

Toxicity assessmentsToxicity assessmentsChemicals with adequate toxicity dataChemicals with adequate toxicity dataChemicals with limited toxicity dataChemicals with limited toxicity data

Toxicity AssessmentToxicity Assessment

The basic objective of a toxicity The basic objective of a toxicity assessment is to identify what adverse assessment is to identify what adverse health effects a chemical causes and how health effects a chemical causes and how the appearance of these adverse effects the appearance of these adverse effects depends on exposure level (dose)depends on exposure level (dose)

TCEQ Exposure Durations and TCEQ Exposure Durations and Averaging TimesAveraging Times

Acute – 1 hour intermittent exposure Acute – 1 hour intermittent exposure (short-term)(short-term)

Chronic – lifetime exposure (long-term)Chronic – lifetime exposure (long-term)

Tiered Approach for Chemicals Tiered Approach for Chemicals with Limited Toxicity Informationwith Limited Toxicity Information

Tier IEmission Controls

(Best-Available-Control Technology)Threshold of Regulation

default ESL = 1µg/m3

Time and Resource Requirements

Tox

icity

Info

rmat

ion

Com

plex

ity o

f Dec

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n

Tier IIIRelative Toxicity/Potency Approach

generic ESL

Tier IIThreshold of Concern Approach

Use LC50 Data

generic ESL

Cumulative Normal DistributionCumulative Normal Distribution

Threshold of Concern ApproachThreshold of Concern Approach

Threshold of Concern ApproachThreshold of Concern Approach

Obtain LCObtain LC5050 data and acute inhalation NOAELs data and acute inhalation NOAELs from animal studies for 97 chemicalsfrom animal studies for 97 chemicals

Exposure duration: 1-hour intermittent Exposure duration: 1-hour intermittent exposure, but frequently included > 1 hr studies, exposure, but frequently included > 1 hr studies, and in some cases multiple day studiesand in some cases multiple day studies

Categorize chemicals into different acute Categorize chemicals into different acute inhalation toxicity potency classes using LCinhalation toxicity potency classes using LC5050 data and the Globally Harmonized System data and the Globally Harmonized System (GHS) of Classification and Labeling of (GHS) of Classification and Labeling of Chemicals (United Nations 2005)Chemicals (United Nations 2005)

Threshold of Concern (TOC)Threshold of Concern (TOC)Table 3-3. Threshold of Concern Approach for Determining Tier II Generic Short-Term ESLs• Globally Harmonized System of Classification and Labeling of Chemicals (GHS)

• Category 1 • Category 2 • Category 3 • Category 4 • Category 5

• Skin Irritation • Corrosive • Irritant • Mild Irritant

• Eye Irritation • Causes serious eye damage

• Causes serious eye irritation

• Causes mild to moderate eye irritation d

Oral LD50

mg/kg

0 to < 5 a > 5 to < 50 a > 50 to < 300 a > 300 to < 2000 a > 2,000 a

• LC50

• gas• ppmv

• 0 to < 100 • > 100 to < 500 • > 500 to < 2500 • > 2500 to < 5000 • > 5,000

LC50

dust & mists b

• mg/m3

• 0 to < 50 • > 50 to < 500 • > 500 to < 1000 • > 1000 to < 5000 • > 5,000

• LC50

• vapors c

• mg/m3

• 0 to < 500 • > 500 to < 2000

• > 2000 to < 10,000 • > 10,000 to < 20,000 • > 20,000

• Generic Short-Term ESL

• 4 µg/m3 • 20 µg/m3 • 125 µg/m3 • 125 µg/m3 • 1000 µg/m3

Cat 3&4 =12.6 mg/m3

Cat 5 = 104 mg/m3Cat 2 = 2 mg/m3

Cat 1 = 0.4 mg/m3

Calculate the 10th percentile of the cumulative Calculate the 10th percentile of the cumulative percentage distribution of NOAELs in each categorypercentage distribution of NOAELs in each category

Threshold of Concern (TOC)Threshold of Concern (TOC)

Divide the 10Divide the 10thth percentile NOAEL values by percentile NOAEL values by 100 to account for human variability and 100 to account for human variability and uncertainty of animal to human extrapolationuncertainty of animal to human extrapolation

Cat 1: 0.4 mg/m3 / 100 = 4 ug/m3

Cat 2: 2 mg/m3 / 100 = 20 ug/m3

Cat 3&4: 12.6 mg/m3 / 100 = 125 ug/m3

Cat 5: 104 mg/m3 / 100 = 1000 ug/m3

Use the LCUse the LC5050 data of a chemical to categorize it data of a chemical to categorize it into a GHS category. Use the TOC for that into a GHS category. Use the TOC for that category as a generic ESLcategory as a generic ESL

Tier II Generic ESLsTier II Generic ESLsNOAEL to LCNOAEL to LC5050 Ratio Approach Ratio Approach

NOAEL-to-LCNOAEL-to-LC5050 Ratio Ratio

10th percentile ratio = 0.0083

Calculate the ratio between acute inhalation NOAELs and LC50

Calculate the 10th percentile ratio

NOAEL-to-LCNOAEL-to-LC5050 Ratio Ratio

Divide the ratio of 0.0083 by 100 to Divide the ratio of 0.0083 by 100 to account for human variability and account for human variability and uncertainty of animal to human uncertainty of animal to human extrapolationextrapolation

Health-Protective Ratio = 0.000083Health-Protective Ratio = 0.000083

LCLC5050 data x 0.000083 = data x 0.000083 =

generic ESLgeneric ESL

TOC or TOC or NOAEL-to- LCNOAEL-to- LC5050 Ratio Approach? Ratio Approach?Both approaches use LCBoth approaches use LC5050 data, although the data, although the TOC approach is generally more conservative TOC approach is generally more conservative than the NOAEL-to- LCthan the NOAEL-to- LC5050 Ratio approach Ratio approach

Use information on the chemical (i.e., toxicity of Use information on the chemical (i.e., toxicity of chemical class or chemical structure) and a chemical class or chemical structure) and a weight-of-evidence approach to decide which weight-of-evidence approach to decide which approach is most defensibleapproach is most defensible

Choose the most conservative number if there is Choose the most conservative number if there is uncertainty in the quality of the LC uncertainty in the quality of the LC5050 data data

SummarySummary

For chemicals with limited toxicity data, For chemicals with limited toxicity data, statistical or relative toxicity/potency statistical or relative toxicity/potency approaches can be used to derive health-approaches can be used to derive health-protective default or generic ESLsprotective default or generic ESLs

Tier 1 – Threshold of RegulationTier 1 – Threshold of Regulation Tier II – Threshold of Concern toxicity potency classes or Tier II – Threshold of Concern toxicity potency classes or

NOAEL-to-LCNOAEL-to-LC5050 Ratio Ratio

Tier III – Relative Toxicity/Potency ApproachTier III – Relative Toxicity/Potency Approach

QuestionsQuestions

Roberta L. GrantRoberta L. Grantrgrantrgrant@tceq.state.tx.us@tceq.state.tx.us

(512) 239-4115(512) 239-4115

Toxicology Division Website:Toxicology Division Website:http://www.tceq.state.tx.us/implementation/tox/esl/guidelines/http://www.tceq.state.tx.us/implementation/tox/esl/guidelines/

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